Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with IPAH and DaPAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular (RV) failure and death has not been tested. Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with severe PAH and NYHA class IV symptoms includes use of MR antagonists for their diuretic and natriuretic effects, late in the course, once clinical right heart failure has developed. Currently, no well described data exists from randomized clinical trials examining the safety and efficacy of MR antagonist therapy in early stages of PAH. Subjects with IPAH and DaPAH in this randomized, double blinded, placebo-controlled study of early treatment with spironolactone undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) plasma profiling of inflammatory markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5) high-resolution MRI-based determination of pulmonary vascular and RV structure and function. Safety and tolerability of spironolactone in PAH is assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects. We hypothesize that initiating therapy with spironolactone at an earlier stage of disease in subjects with PAH could provide additional benefits through anti-inflammatory effects and improvements in pulmonary artery endothelial function. The concept for the protocol received an NIH Bench-to-Bedside Award in 2011 and a formal protocol was initially approved by the NHLBI IRB in September 2012. Subsequently IRB approval was sought and obtained at collaborating sites and various amendments were brought into alignment at all institutions by summer 2013. In 2013 -15 we established at the NIH a clinical research PAH program consisting of a multidisciplinary medical staff with expertise in cardiology, pulmonary, and critical care as well as a regulatory and research nursing support staff with extensive experience in assuring compliance with clinical protocols while maintaining the highest standards of clinical care. Referrals are currently being received from multiple sites. To date of the 30 pulmonary hypertension subjects enrolled in our Natural History protocol (13-CC-0012) thirteen have been enrolled in this study (Spironolactone Randomized Interventional Trial). This randomized controlled trial is double blinded and open for recruitment. Plans for bolstering recruitment and increasing enrollment include: 1) Received NHLBI IRB approval for an information card (Icard) we developed highlighting essential details of our study. We plan on providing the Icard to potential communities of interest. 2) Received approval from the Office of Communications and Media Relations and the NHLBI IRB to develop a web page on the NIH web site highlighting our NIH PAH program. 3) Presented our trial in the Research Room at the Pulmonary Hypertension Association (PHA) 2016 International PH Conference and Scientific Sessions. We handed out the Icards to patients, health care providers and other parties of interest. 4) Continue to present our study to local pulmonary hypertension support groups. 5) Research nurses continue to conduct periodic visits to local referral sites in order to facilitate communication with clinic staff and PAH patients. 6) Continue to reach out to regional academic centers and clinical practices. 7) In collaboration with the Department of Clinical Research Informatics (DCRI) we plan on developing a smart phone application that will allow a health care provider or a patient to easily discern the essentials of our protocol and determine if the patient qualifies for the protocol.